Project Summary 60% of women will suffer from a urinary tract infection (UTI) at some point in their lives and a third of women with an acute UTI will suffer recurrent UTIs. This disease is especially problematic for post-menopausal women where over 50% will have recurrent infections that cannot be cured with antibiotics. This increased susceptibility is likely due to reduced estrogen levels that accompany aging. However, the mechanisms behind this increased susceptibility are unknown, and this lack of knowledge impedes our ability to develop new strategies for the treatment and prevention of UTIs, especially in post-menopausal women. Here, we focus on the cytokine, interleukin-6 (IL-6), which is rapidly upregulated during UTIs in humans, and multiple studies have shown that postmenopausal women have elevated serum levels of IL-6. Recent studies indicate that IL-6 signaling not only modulates innate immune responses but also is essential for timely wound healing and tissue regeneration. In preliminary studies, we demonstrate that loss of IL-6 impairs the host response to UPEC and that aged female mice exhibit high levels of IL-6, increased recruitment of macrophages, and impaired tissue repair. Our objective here is to determine how balance is achieved between 1) activating the innate immune system (macrophages) to destroy the pathogen (predominantly uropathogenic E. coli [UPEC]) and 2) repairing the bladder epithelium. We will test the central hypothesis that IL-6 is a key regulator of the balance between host defense and epithelial homeostasis. In Aim 1, we will dissect the function of IL-6 signaling in modulating the immune and epithelial response to a UTI and how loss of function of this protein impairs host defense response. In Aim 2, we will determine the mechanisms whereby aging influences UTI outcomes. Importantly, we will leverage our mechanistic insights to determine whether selective estrogen receptor agonists or anti-IL6 therapies will be effective treatments. We anticipate that our work will provide new insights into the molecular interplay between estrogen and bladder host defense during a UTI. In addition, the experiments will provide a foundation upon which to determine whether estrogen and anti-IL-6 therapies will be effective interventions in post-menopausal women suffering from chronic, recurrent UTIs and will help to develop preventive interventions and treatments that are optimized for menopausal women.